Wednesday, June 4, 2008

mdash; Mayo Clinic researchers and collaborators say they have conclusively demonstrated that a substantial subset of colon cancer patients should not receive chemotherapy because it provides no clinical benefit, and actually may reduce survival time.

Research findings indicate that oncologists should use an existing test to check tumor subtype in certain patients before offering treatment. Patients who would benefit most from this test include those with locally advanced disease that has not spread to their lymph nodes, known as stage II disease.

The study, released May 15 as part of the 44th annual meeting of the American Society of Clinical Oncology, found that the 15 percent of patients with tumors defined as "deficient DNA mismatch repair" (dMMR) do not respond to 5-fluorouracil (5-FU) chemotherapy, which is widely used to treat colon cancer.

The researchers and collaborators published a study in 2003 in the New England Journal of Medicine (NEJM) http://www.ncbi.nlm.nih.gov/pubmed/12867608) (http://www.ncbi.nlm.nih.gov/pubmed/12867608) that suggested patients with dMMR tumors should not be treated with chemotherapy. Because the finding was so novel, confirmation of the results was required before they could be incorporated into clinical practice. This new work offers that confirmation.

"We think it is very important for patients and their doctors to have this information before considering treatment in a patient with stage II colon cancer," says Daniel Sargent, Ph.D., a Mayo Clinic biostatistician who is presenting the study results. "It could save patients the toxicity, inconvenience and expense of treatment from which they will receive no benefit."

Simple laboratory tests for dMMR exist. They are currently used to check for hereditary colon cancer that also is characterized by the absence of mismatch repair proteins, says coauthor Stephen Thibodeau, Ph.D.

"Many clinical laboratories across the country already use these tests," he says. "Now that this study proves the case that dMMR testing should be part of standard diagnostic practice for the treatment of colon cancer, this can be easily incorporated into a clinical workup."

Researchers know that colon cancer can be divided into at least two major groups. About 15 percent of tumors demonstrate the inability to correct damage to DNA by an important error-checking mechanism called DNA mismatch repair (dMMR tumors). The remaining 85 percent have different genetic alterations and exhibit another type of cellular problem called chromosomal instability.

In addition to different types of cellular problems, these two tumor groups seem to behave quite differently in patients. "It has been known for some time now that patients whose tumors have dMMR do better. The tumors are somewhat less aggressive, and they tend to occur later in life," says Dr. Sargent. "Overall, these patients have a better prognosis.

"This study is important because it looks more carefully at how these patients respond to chemotherapy," he says. "This study now provides convincing data to show that a subset of patients with dMMR tumors do not benefit from treatment. Without treatment, patients with dMMR tumors have a better prognosis compared to patients with chromosomal instability."

To ensure the original NEJM findings were reliable — a finding that could change clinical practice — the researchers spent years finding patients who had not been treated with 5-FU, and then analyzed how well these patients responded in relation to tumor subtype. "We had to develop an international collaboration, with multiple groups in the United States and Europe contributing both data and biospecimens from many different studies," says Dr. Sargent. "We felt that because our initial finding was clinically important to patients, this validation study was critical."

The research team studied tissue specimens from 1,027 patients. Sixteen percent were classified as having dMMR. The study showed that those patients whose tumors had the chromosomal instability type benefited significantly from chemotherapy. These chemotherapy-treated patients had a five-year survival of 74 percent compared to 66 percent in untreated patients.

But chemotherapy treatment did not help patients with dMMR. Researchers found that patients who had stage II disease with tumors defined as dMMR had significantly worse five-year survival (75 percent) if they were treated with standard 5-FU-based chemotherapy compared to patients who were not treated (93 percent survival).

Research is ongoing to understand why patients with dMMR tumors can have a worse prognosis after chemotherapy treatment. One theory, according to Drs. Sargent and Thibodeau, is that because these cancer cells cannot repair damage from chemotherapy, the treatment induces mutations that can cause the cancer to become more aggressive. Another theory is that while these cancers produce a strong innate immune reaction, chemotherapy may dampen that beneficial response, resulting in increased cancer growth.

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